Asthma which has been hitherto considered as a reversible obstruction of airway is currently understood as a disease characterized by airway hypersensitivity and airway obstruction derived from chronic airway inflammation involving a number of inflammatory cells. The number of the patients has been increasing steadily and is predicted to further increase hereafter.
For the treatment of asthma, inhale steroid drugs as antiinflammatory agents, and β-stimulants such as procaterol and xanthine derivatives such as aminophylline and theophylline as bronchodilators are now mainly used.
The inhale steroid drugs have a wide antiinflammatory action and are highly useful as asthma-treating drugs, but the necessity of instructing an appropriate inhalation method and the existence of steroid-resistant asthma patients have been pointed out (ASTHMA 13-1, 69–73 (2000), Internal Medicine, 81, 485–490 (1998)).
The bronchodilators alleviate contraction of airway smooth muscle by increasing intracellular cyclic adenosine 3′,5′-monophosphate (cAMP) concentration through the activation of an intracellular CAMP producing enzyme, adenylate cyclase, or the inhibition of a CAMP hydrolyzing enzyme, phosphodiesterase (PDE) in airway smooth muscle (Internal Medicine, 69, 207–214 (1992)). It is known that increased intracellular CAMP concentration induces inhibition of the contraction of airway smooth muscle (Clin. Exp. Allergy, 22, 337–344 (1992), Drugs of the Future, 17, 799–807 (1992)), which is effective in improving conditions of asthma.
However, it is known that the xanthine derivatives express systemic side effects such as hypotension and cardiotonic action (J. Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551–564 (1985), J. Pharmacol. Exp. Ther., 257, 741–747 (1991)), and the β-stimulants are apt to cause desensitization and, when the dosage is increased, generate side effects such as finger tremor and palpitation.
On the other hand, chronic obstructive pulmonary disease (COPD) is a respiratory disease which relates to an abnormal inflammatory reaction and is characterized by irreversible limitation of airflow, and is the fourth cause of death in the world at present (Executive summary. Global Initiative for Chronic Obstructive Lung Disease (GOLD), (2000)). Currently, as in the case of asthma, β-stimulators, anticholinergic drugs, and xanthine derivatives such as aminophylline and theophylline as bronchodilators are now generally used as drug therapy for COPD. In addition, inhale steroid drugs are also used since attention has been attracted to the fact that the presence of chronic inflammation in airway participates in the obstructive disorder also in COPD, but it has been reported that continuous treatment with inhale steroid does not improve the long-term decrease of FEV1 in COPD patients (N. Engl. J. Med. 340, 1948–53 (1999), Lancet 353, 1819–23 (1999), BMJ 320, 1297–303 (2000), N. Engl. J. Med. 343, 1902–9 (2000)). Thus, an antiinflammatory drug capable of improving conditions of COPD is highly desired.
It has been revealed that PDE is divided into at least seven families of from PDE1 to PDE7, and each of them has different distribution or function (Prog. Nucleic Acid Res. Mol. Biol. 63, 1–38 (1999)). Particularly, PDE4 does not act upon cyclic guanosine 3′,5′-monophosphate (cGMP) but specifically hydrolyze cAMP among nucleotides, and its presence is recognized in both of airway smooth muscle and infiltrating cells.
Also, it has been reported that PDE4 inhibitors show inhibitory action upon eosinophiles infiltration by antigens and platelet-activating factors in guinea pig (Eur. J. Pharmacol., 255, 253–256 (1994)) and inhibit liberation of detrimental proteins (MBP, ECP) from eosinophiles (Br. J. Pharmacol., 115, 39–47 (1995)). It has been also reported that they show inhibitory action upon the contraction of airway smooth muscle by contractile substances (histamine, methacholine, LTD4) (Br. J. Pharmacol., 113, 1423–1431 (1994)), inhibit production of IL-4, a cytokine which is said to deeply participate in asthma (J. Invest. Dermatol., 100, 681–684 (1993)), express inhibitory action upon the acceleration of vascular permeability in the airway (Fundam. Clin. Pharmacol., 6, 247–249 (1992)) and show inhibitory action upon airway hypersensitivity (Eur. J. Pharmacol., 275, 75–82 (1995)). Thus, a PDE4 inhibitor is expected to be an asthma-treating agent.
Moreover, it has been reported that PDE4 inhibitors have infiltration inhibitory action upon neutrophiles which are considered to be involved in airway inflammation in COPD (Pulm. Pharmacol. Ther. 2001 March; 14(2): 157–164). Furthermore, PDE4 inhibitors are capable of improving respiratory function of COPD patients (Clin. Exp. Allergy. 1999 June; 29 Suppl 2: 99–109). Thus the inhibitor is also expected to be a COPD-treating drug.
As a compound having PDE4 inhibitory activity, the following compound:
(wherein A, Y and B mean each a bond or the like, Z means a pyridine ring or the like which may be substituted with R3, R3 means CONR4R5 or the like, and R4 and R5 represent each (1) a saturated or unsaturated five- or six-membered heterocycle which may be substituted with one or two groups selected from C1-4 alkyl, CO2R7, CONH2, CON(CH3)2, oxo, OH, NH2 and N(CH3)2, (2) a saturated or unsaturated six-membered heterocycle having one hetero atom as an additional ring atom selected from O, S, NH, NCH3, NCOCH3 or NCH2Ph, or (3) a quinoline ring which may be substituted by fluorine, or the like) is disclosed in WO 94/12461. However, a part of phenylpyridinecarbonylpiperazine derivatives are included in the wide claims of the publication but no specific compound thereof is described therein. Even as phenylpyridinecarboxamide derivatives, the publication only describes the following 5-phenylpyridine-3-carboxamide.
